Immunologically active peptidyl disaccharides and methods of preparation

Abstract

2-Amino-2-deoxy- beta -D-glucopyranosyl-(1-4)-2-amino-2-deoxy-D-glucoses of the general structural formula: <IMAGE> wherein R1 is hydrogen, alkyl (1-7C), substituted alkyl (1-7C), phenyl, substituted phenyl, benzyl, or substituted benzyl; R2 is alkyl, substituted alky, phenyl, or substituted phenyl and each R2 may be the same group or a different group; R3 is H or <IMAGE> wherein R8 is H or lower alkyl (1-10C), and provided at least one of R3 is not H, R9 is H, or R9-R10 together is -CH2-CH2-CH2-; R10 is H, alkyl (L-7C), hydroxymethyl, mercaptomethyl, benzyl, or substituted benzyl; R11 and R12 each is carboxyl, esterified carboxyl (1-7C), amidated carboxyl, or mono- or di-alkyl- (1-3C) amidated carboxyl; R4 and R5 are the same or different and are H, aliphatic or aromatic acyl (2-21C) or substituted acyl (2-21C); when R8 is lower alkyl, the stereochemistry at asymmetric center I can be either D or L; when R10 is not H, the stereochemistry at asymmetric center II is L; the stereochemistry at asymmetric center III is D. These compounds possess immunostimulatory properties.

What is claimed is: 
     
       1. A 2-amino-2-deoxy-β-D-glucopyranosyl-(1→4)-2-amino-2-deoxy-D-glucose of the general structural formula: ##STR14## wherein R 1  is hydrogen, alkyl (1-7C), substituted alkyl (1-7C) wherein the substituent is hydroxy, mercapto, alkoxy of 1-3 carbons, alkyl mercapto of 1-3 carbons, hydroxy or mercapto esterified by an acid of 1-4 carbon atoms, F, Cl, Br, carboxyl, or carboxyl functionally modified by esterification with an alcohol of 1-3 carbons or by amidation, phenyl, substituted phenyl wherein the substituent is an alkyl group of 1-3 carbons, hydroxy, mercapto, hydroxy or mercapto etherified by an alkyl group of 1-3 carbons, hydroxy or mercapto esterified by an acid of 1-4 carbons, alkyldioxy (1-4C), cycloalkyldioxy (5-7C), amino or trifluoromethyl, benzyl, or substituted benzyl wherein the substituent is an alkyl group of 1-3 carbons, hydroxy, mercapto, hydroxy or mercapto etherified by an alkyl group of 1-3 carbon atoms, hydroxy or mercapto esterified by an acid of 1-4 carbons, alkyldioxy (1-4C), cycloalkyldioxy (5-7C), amino or trifluoromethyl; R 2  is alkyl (1-7C), substituted alkyl (1-7C) wherein the substituent is hydroxy, mercapto, alkoxy of 1-3 carbons, alkylmercapto of 1-3 carbons, hydroxy or mercapto esterified by an acid of 1-4 carbon atoms, F, Cl, Br, carboxyl, or carboxyl functionally modified by esterification with an alcohol of 1-3 carbons or by amidation, phenyl, or substituted phenyl wherein the substituent is an alkyl group of 1-3 carbons, hydroxy, mercapto, hydroxy or mercapto etherified by an alkyl group of 1-3 carbon atoms, hydroxy or mercapto esterified by an acid of 1-4 carbons, alkyldioxy (1-4C), cycloalkyldioxy (5-7C), amino or trifluoromethyl and each R 2  may be the same group or a different group;   R 3  and R' 3  are H or ##STR15## wherein R 8  is H or lower alkyl (1-10C), and provided at least one of R 3  and R' 3  is not H;   R 9  is H, or R 9  -R 10  together is --CH 2  CH 2  CH 2  --;   R 10  is H, alkyl (1-7C) hydroxymethyl, mercaptomethyl, benzyl, or substituted benzyl wherein the substituent is an alkyl group of 1-3 carbon atoms, hydroxy, mercapto, hydroxy or mercapto etherified by an alkyl group of 1-3 carbons, hydroxy or mercapto esterified by an acid of 1-4 carbons, alkyldioxy (1-4C), cycloalkyldioxy (5-7C), amino or trifluoromethyl;   R 11  and R 12  each are independently carboxyl, esterified carboxyl (1-7C), amidated carboxyl, or mono- or di-alkyl (1-7C) amidated carboxyl;   R 4 , R 5  and R' 5  are the same or different and are H, aliphatic or aromatic acyl (2-21C) or substituted acyl (2-21C) wherein the substituent is halogen, alkyl (1-3C), alkoxy (1-3C), trifluoromethyl, hydroxy, alkanoyloxy (1-3C),   provided when R 8  is loweralkyl, the stereo chemistry at asymmetric center I can be either D or L; and when R 10  is not H, the stereochemistry at asymmetric center II is L; the stereochemistry at asymmetric center III is D; provided further when R 1 , R 5 , R' 3 , R 4 , and R' 5  are each H and each R 2  is CH 3 , R 3  is not H 3  CCHCOR 13  wherein R 13  is a dipeptide.     
     
     
       2. A compound of claim 1 wherein R 2  is methyl. 
     
     
       3. A compound of claim 1 wherein R 1  and R 5  are hydrogen, and R 4  and R' 5  are hydrogen or acetyl. 
     
     
       4. A compound of claim 1 wherein R 3  and R' 3  are H or ##STR16## 
     
     
       5. A compound of claim 2 wherein R 1 , R 3 , R 4 , R' 5  and R 5  are hydrogen and R' 3  is ##STR17## 
     
     
       6. A compound of claim 2 wherein R 1  and R 3  and R 5  are hydrogen, R 4  and R' 5  are acetyl and R' 3  is ##STR18## 
     
     
       7. A compound of claim 2 wherein R 1  R' 3 , R 4 , R' 5  and R 5  are hydrogen and R 3  is ##STR19## 
     
     
       8. A compound of claim 1 wherein R 1  is H, alkyl of 1-3 carbons, benzyl, phenyl or phenyl p-substituted by alkyl (1-3C), amino, F, Cl, Br, hydroxy or trifluoromethyl; R 2  is alkyl of 1-3 carbons, or phenyl, or phenyl p-substituted by alkyl (1-3C), amino, F, Cl, Br, hydroxy or trifluoromethyl; R 3  is H, R 4  and R 5  are H, alkanoyl of 2-21 carbons, benzoyl or naphthoyl; R 10  is H, alkyl or 1-4 carbons, hydroxymethyl, mercaptomethyl, benzyl or p-hydroxybenzyl; R 9  and R 10  together are --CH 2  CH 2  CH 2  --; and R 11  and R 12  are carboxyl, carboxyl esterified by an alcohol of 1-4 carbons, carboxamide, or monoalkyl or dialkyl substituted carboxamide wherein the alkyl group has from 1-3 carbons. 
     
     
       9. Compounds of the formula ##STR20## wherein Ac is a residue of an aliphatic carboxylic acid having at least 3 carbon atoms; and R is a dipeptide. 
     
     
       10. A composition having immunostimulatory properties comprising a compound of claim 1 in an amount effective to produce an immunostimulatory effect and a pharmaceutically acceptable carrier. 
     
     
       11. An antibacterial composition comprising a compound of claim 1 in an amount effective to produce an antibacterial effect and a physiologically acceptable medium. 
     
     
       12. A composition of claim 10 in aqueous formulation. 
     
     
       13. A composition of claim 10 in oil formulation.